Chronic tobacco use can lead to nicotine addiction, which is characterized by compulsive nicotine taking behaviors with loss of control and high relapse frequency. Notably, nicotine serves as a gateway and its use can lead to addiction to alcohol, cocaine and possibly other addictive drugs. Nicotine use is also associated with lung cancer and cardiovascular events, such as stroke, hypertension, myocardial infarction, and sudden death. Despite these negative health consequences, a limited number of pharmacotherapeutic agents are available to treat nicotine addiction. In some cases, these medications are not effective or cause similar adverse effects as smoking tobacco. Thus, novel key mechanisms and pathways that facilitate the aversive effects of nicotine and/or reduce its rewarding and reinforcing actions need to be characterized since they can be potential targets for the development of pharmacotherapy to curb nicotine addiction. Likewise, drugs that reduce the negative affective states associated with nicotine withdrawal can be potential pharmacotherapeutic candidates for smoking cessation.

Pituitary adenylyl cyclase activating polypeptide (PACAP) and its receptors (PAC1, VPAC1 and VPAC2) are found in brain regions implicated in stress response, reward, motivated behaviors and, importantly, in nicotine dependence and addiction. Thus, we hypothesized that PACAP is involved in the rewarding and/or aversive effects of nicotine.

Our work is relevant to the basic science of nicotine dependence. Our preliminary data show that PACAP is involved in nicotine-induced aversion using the place conditioning and the two-bottle choice paradigms. Thus, the PACAP/PAC1 receptor system may be a potential target for the development of pharmacotherapy to treat nicotine addiction.